Colony context and size-dependent compensation mechanisms give rise to variations in nuclear growth trajectories.

To investigate the fundamental question of how cellular variations arise across spatiotemporal scales in a population of identical healthy cells, we focused on nuclear growth in hiPS cell colonies as a model system. We generated a 3D timelapse dataset of thousands of nuclei over multiple days, and developed open-source tools for image and data analysis and an interactive timelapse viewer for exploring quantitative features of nuclear size and shape. We performed a data-driven analysis of nuclear growth variations across timescales. We found that individual nuclear volume growth trajectories arise from short timescale variations attributable to their spatiotemporal context within the colony. We identified a strikingly time-invariant volume compensation relationship between nuclear growth duration and starting volume across the population. Notably, we discovered that inheritance plays a crucial role in determining these two key nuclear growth features while other growth features are determined by their spatiotemporal context and are not inherited.

The Brief Evaluation of Adolescents and Children Online (BEACON): Psychometric development of a mental health screening measure for school students.

This paper describes the development and psychometric evaluation of a brief self-report measure (BEACON) to inform universal mental health screening in schools. Items assess symptoms and impairment associated with anxiety and attention/hyperactivity problems (grades 4-11) as well as depression and eating difficulties (grades 6-11), with optional items for suicidality and self-harm (grades 7-11). Initial item examination based on Item Response Theory (IRT) and classical test theory involved 3844 students in grades 4 through 11 (Study 1) and identified 18 items for grades 4-5 and 31 items for grades 6-11 that fulfilled pre-set criteria. Study 2 extended testing with 10,479 students in grades 4-11 and added an additional four items assessing impairment associated with eating difficulties for older students (grades 6-11) creating a total of 35 items for grades 6-11. All items, for both grade-level versions, met the pre-set criteria for IRT and classical test theory analysis supporting their strength in the measurement of the dimensions of concern. The measure showed good reliability (subscale alphas .87 to .95). Validity was also demonstrated against standard symptom measures, school grades, school absenteeism, and help-seeking. The BEACON appears to be a psychometrically sound measure to use in the first stage of school-based screening for mental health problems.

How are evidence generation partnerships between researchers and policy-makers enacted in practice? A qualitative interview study.

BACKGROUND: Evidence generation partnerships between researchers and policy-makers are a potential method for producing more relevant research with greater potential to impact on policy and practice. Little is known about how such partnerships are enacted in practice, however, or how to increase their effectiveness. We aimed to determine why researchers and policy-makers choose to work together, how they work together, which partnership models are most common, and what the key (1) relationship-based and (2) practical components of successful research partnerships are. METHODS: Semi-structured qualitative interviews were conducted with 18 key informants largely based in New South Wales, Australia, who were (1) researchers experienced in working in partnership with policy in health or health-related areas or (2) policy and programme developers and health system decision-makers experienced in working in partnership with researchers. Data was analysed thematically by two researchers. RESULTS: Researcher-initiated and policy agency-initiated evidence generation partnerships were common. While policy-initiated partnerships were thought to be the most likely to result in impact, researcher-initiated projects were considered important in advancing the science and were favoured by researchers due to greater perceived opportunities to achieve key academic career metrics. Participants acknowledged that levels of collaboration varied widely in research/policy partnerships from minimal to co-production. Co-production was considered a worthy goal by all, conferring a range of benefits, but one that was difficult to achieve in practice. Some participants asserted that the increased time and resources required for effective co-production meant it was best suited to evaluation and implementation projects where the tacit, experiential knowledge of policy-makers provided critical nuance to underpin study design, implementation and analysis. Partnerships that were mutually considered to have produced the desired outcomes were seen to be underpinned by a range of both relationship-based (such as shared aims and goals and trust) and practical factors (such as sound governance and processes). CONCLUSIONS: Our findings highlight the important role of policy-makers in New South Wales in ensuring the relevance of research. There is still much to understand about how to initiate and sustain successful research/policy partnerships, particularly at the highly collaborative end.

Examining the role of a decision aid in reducing decisional conflict amongst hospital healthcare workers towards receiving the influenza vaccine.

BACKGROUND: Currently the uptake of the influenza vaccine amongst Australian hospital staff remains low. While some staff members choose not to receive the vaccine, others may feel decisional conflict around whether to receive the vaccine or not. Having access to information that is personalized to the staff members' concerns may alleviate this conflict. Our study aimed to explore the attitudes of hospital staff towards an online decision aid (DA), which focuses on influenza and the vaccine. We were also interested to examine whether they accepted the new tool and whether they had any suggestions for improvements. METHODS: Forty-one semi-structured interviews were undertaken with a range of hospital staff from two major public hospitals in Sydney and Melbourne, Australia in 2013. Emails and posters were used to inform staff members about the study. Thematic analysis was performed to explore the attitudes of hospital staff towards the DA. RESULTS: Our participants were well aware of the time/location of the staff vaccination clinics, however very few reported attending or receiving any educational material about the disease or the vaccine. Amongst those who did receive material, they felt that the messages were "dumbed down". There was a mostly positive response to the DA from participants, however they felt that unless it was included as part of mandatory training or orientation, it would be difficult to get staff to use the tool. CONCLUSIONS: Previous studies have established that education is an important component of an influenza vaccination program. We believe that the decision aid offers an alternative approach to delivering balanced information to staff members, which may reduce workload burdens on administrators and drive up rates.

Participation in clinical supervision (PACS): an evaluation of student nurse clinical supervision facilitated by mental health service users.

This paper discusses an innovative learning approach in which people having experience of mental health services facilitated humanistic clinical supervision with groups of student nurses in the classroom. A four-day course of preparation for the role of supervisor is described and the results of subsequent clinical supervision sessions are analysed. Seven service users who had previous experience of teaching students in the classroom and fifty students on a Diploma/BSc in mental health nursing course participated in the project, which was evaluated through focus groups. The results indicated that the service user supervisors appreciated the skills they had gained on the course and felt that they were more appropriate than lecturers to facilitate clinical supervision sessions. Some students expressed initial uncertainty about the appropriateness of service users as supervisors but as changes to the pedagogical process of supervision were made and the supervisors gained more experience and confidence, students expressed greater satisfaction. The authors conclude that clinical supervision facilitated by service users who have preparation and continual support can add considerable value to the learning experience of student nurses.

Welwitindolinone C synthetic studies. Construction of the welwitindolinone carbon skeleton via a transannular nitrone cycloaddition.

Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that employs a sequential rhodium carbenoid-mediated O-H insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition.

Nurse specialist treatment of eye emergencies: five year follow up study of quality and effectiveness.

The role of specialist nurses in triage, diagnosis and management of emergency eye conditions is well established, and encouraging reports of the safety and effectiveness of such services have been published. Specialist nurses in an emergency eye clinic in the UK seeing >7000 patients per year had been found at initial evaluation to treat 22% of the 1976 patients seen over a three month period without referring on to an ophthalmologist. A repeat of this evaluation five years later found this proportion had dropped to 17% (chi(2) = 16.7, p<0.01). In addition, the initial evaluation had found no incident of any patient having been treated and discharged by the specialist nurses returning to the department due to incorrect diagnosis or mismanagement. By contrast, from the sample 5 years later, 3 patients were identified who returned to the department due to possible misdiagnosis or sub-optimal management. We suggest that provision must be made for continuing professional development of nurses in this type of extended role, and the commitment to ongoing education should be backed up by a system of monitoring and critical incident reporting to facilitate skill maintenance and the life long learning process for specialist nurses.

Patient perspective: what do palliative care patients think about their care?

Developing accountable and appropriate care services depends on listening to the views of service users. This nurse-led, qualitative study explored 10 palliative care patients' views of their care in hospital and at home using non-standard interviews. A total of 10 categories emerged, some of which are not reflected well in extant literature. However, some smaller studies show comparable results, which confirms the validity of these findings. These findings can inform the planning of services and are repeatable and generalizable. Implications for nursing and planning for palliative care are discussed.

Risk factors and seroprevalence of markers for hepatitis A, B and C in persons subject to homelessness in inner Sydney.

OBJECTIVE: To determine the seroprevalence of hepatitis A, B and C and the prevalence of risk factors for blood-borne infections in persons subject to homelessness attending a medical clinic in inner Sydney. METHOD: During 2003-05, 201 clients were enrolled in a prospective study to determine the acceptance, completion rates and immunogenicity of the standard vaccination schedule for hepatitis A and B. On enrolment, clients completed a risk factor assessment questionnaire and undertook pre-vaccination serological screening for hepatitis A, B and C. RESULTS: Forty-five per cent (85/188) of clients were positive for anti-HCV antibodies; 32% (60/189) showed evidence of past infection with HBV (anti-HBc); and 48% (89/189) were positive for anti-HAV antibodies. It was not uncommon for clients to have multiple markers of hepatitis. A past history of injecting drug use was significantly associated with markers for hepatitis B and C; age predicted presence of anti-HAV. A verbal history of infection appeared more reliable for hepatitis C, but considerably less so for hepatitis A and B. CONCLUSION: Persons subject to homelessness are at risk of blood-borne infection. The seroprevalence of markers for hepatitis B and C are higher than in the general population. IMPLICATIONS: Despite the high proportion of clients with serological markers for hepatitis A and B, at least 69% of clients could potentially benefit from hepatitis A and/or B vaccination.

SAR of a novel 'Anthranilamide Like' series of VEGFR-2, multi protein kinase inhibitors for the treatment of cancer.

Novel anthranilamides were surprisingly found to exert additional activity on B-RAF. Corresponding thiophene, pyrazole, and thiazole core analogs were prepared as VEGFR-2 inhibitors with c-KIT, and B-RAF activity. Compounds in the phenyl, thiophene, and thiazole series are in vivo active.

Glomeruloid hemangioma leading to a diagnosis of POEMS syndrome.

POEMS is an acronym for polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. It is a poorly understood paraneoplastic syndrome that stems from an underlying plasma cell dyscrasia. Of the skin changes, the glomeruloid hemangioma is considered to be a specific marker of POEMS syndrome. We describe a 68-year-old man who presented to his dermatologist with multiple hemangiomas, whose biopsy diagnosis of glomeruloid hemangioma resulted in further evaluation and an eventual diagnosis of POEMS.

The F-Box DNA helicase Fbh1 prevents Rhp51-dependent recombination without mediator proteins.

A key step in homologous recombination is the loading of Rad51 onto single-stranded DNA to form a nucleoprotein filament that promotes homologous DNA pairing and strand exchange. Mediator proteins, such as Rad52 and Rad55-Rad57, are thought to aid filament assembly by overcoming an inhibitory effect of the single-stranded-DNA-binding protein replication protein A. Here we show that mediator proteins are also required to enable fission yeast Rad51 (called Rhp51) to function in the presence of the F-box DNA helicase Fbh1. In particular, we show that the critical function of Rad22 (an orthologue of Rad52) in promoting Rhp51-dependent recombination and DNA repair can be mostly circumvented by deleting fbh1. Similarly, the reduced growth/viability and DNA damage sensitivity of an fbh1(-) mutant are variously suppressed by deletion of any one of the mediators Rad22, Rhp55, and Swi5. From these data we propose that Rhp51 action is controlled through an interplay between Fbh1 and the mediator proteins. Colocalization of Fbh1 with Rhp51 damage-induced foci suggests that this interplay occurs at the sites of nucleoprotein filament assembly. Furthermore, analysis of different fbh1 mutant alleles suggests that both the F-box and helicase activities of Fbh1 contribute to controlling Rhp51.

Thalidomide in the treatment of recalcitrant Sweet's syndrome associated with myelodysplasia.

Sweet's syndrome is a neutrophilic dermatosis characterized by tender, erythematous, pseudovesicular plaques that can be associated with hematologic malignancy. We report a patient with recalcitrant Sweet's syndrome that preceded the development of myelodysplastic syndrome by 30 months. The delay between the onset of Sweet's syndrome and the subsequent diagnosis of myelodysplasia highlights the need for thorough and repeated evaluation for underlying malignancy in patients with such a course. Although corticosteroids are the initial treatment of choice, this patient's eruption was only partially responsive to high-dose prednisone and was refractory to metronidazole, dapsone, and methotrexate. Treatment with thalidomide resulted in complete resolution of the cutaneous lesions within one month of therapy.

VEGF receptor kinase inhibitors: phthalazines, anthranilamides and related structures.

Inhibition of vascular endothelial growth factor receptor (VEGFR) signalling, using either antibodies or small molecule inhibitors of the VEGFR kinase domain, has become a major area of research in oncology. The phthalazine PTK787/ZK222584, first published in the literature in 1998, is one of the most advanced VEGFR inhibitors in the clinic. This paper provides an update on the patenting activity related to the phthalazine class. In addition, newer kinase inhibitor pharmacophores derived from this class (e.g., anthranilamides) will be reviewed.

DNA repair by a Rad22-Mus81-dependent pathway that is independent of Rhp51.

In budding yeast most Rad51-dependent and -independent recombination depends on Rad52. In contrast, its homologue in fission yeast, Rad22, was assumed to play a less critical role possibly due to functional redundancy with another Rad52-like protein Rti1. We show here that this is not the case. Rad22 like Rad52 plays a central role in recombination being required for both Rhp51-dependent and -independent events. Having established this we proceed to investigate the involvement of the Mus81-Eme1 endonuclease in these pathways. Mus81 plays a relatively minor role in the Rhp51-dependent repair of DNA damage induced by ultraviolet light. In contrast Mus81 has a key role in the Rad22-dependent (Rhp51-independent) repair of damage induced by camptothecin, hydroxyurea and methyl-methanesulfonate. Furthermore, spontaneous intrachromosomal recombination that gives rise to deletion recombinants is impaired in a mus81 mutant. From these data we propose that a Rad22-Mus81-dependent (Rhp51-independent) pathway is an important mechanism for the repair of DNA damage in fission yeast. Consistent with this we show that in vitro Rad22 can promote strand invasion to form a D-loop that can be cleaved by Mus81.

Generating crossovers by resolution of nicked Holliday junctions: a role for Mus81-Eme1 in meiosis.

The double Holliday junction (dHJ) is generally regarded to be a key intermediate of meiotic recombination, whose resolution is critical for the formation of crossover recombinants. In fission yeast, the Mus81-Eme1 endonuclease has been implicated in resolving dHJs. Consistent with this role, we show that Mus81-Eme1 is required for generating meiotic crossovers. However, purified Mus81-Eme1 prefers to cleave junctions that mimic those formed during the transition from double-strand break to dHJ. Crucially, these junctions are cleaved by Mus81-Eme1 in precisely the right orientation to guarantee the formation of a crossover every time. These data demonstrate how crossovers could arise without forming or resolving dHJs using an enzyme that is widely conserved amongst eukaryotes.

Cleavage of model replication forks by fission yeast Mus81-Eme1 and budding yeast Mus81-Mms4.

The blockage of replication forks can result in the disassembly of the replicative apparatus and reversal of the fork to form a DNA junction that must be processed in order for replication to restart and sister chromatids to segregate at mitosis. Fission yeast Mus81-Eme1 and budding yeast Mus81-Mms4 are endonucleases that have been implicated in the processing of aberrant DNA junctions formed at stalled replication forks. Here we have investigated the activity of purified Mus81-Eme1 and Mus81-Mms4 on substrates that resemble DNA junctions that are expected to form when a replication fork reverses. Both enzymes cleave Holliday junctions and substrates that resemble normal replication forks poorly or not at all. However, forks where the equivalents of either both the leading and lagging strands or just the lagging strand are juxtaposed at the junction point, or where either the leading or lagging strand has been unwound to produce a fork with a single-stranded tail, are cleaved well. Cleavage sites map predominantly between 3 and 6 bp 5' of the junction point. For most substrates the leading strand template is cleaved. The sole exception is a fork with a 5' single-stranded tail, which is cleaved in the lagging strand template.